Researchers in the United States and Sweden have identified a
genetic region associated with increased risk of rheumatoid arthritis
(RA), a chronic and debilitating inflammatory disease of the joints
that affects an estimated 2.1 million Americans. The U.S. arm of
the study involved a long-time collaboration between intramural
researchers of the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS) and other organizations. NIAMS is one
of 27 institutes and centers at the National Institutes of Health.
The results appeared in the New England Journal of Medicine.

Using the relatively new genome-wide association approach — which
makes it possible to analyze between 300,000 and 500,000 single
nucleotide polymorphisms (SNPs, or small differences in DNA that
are distributed throughout a personís genetic code) — researchers
in both countries searched for genetic differences in blood samples
from people with RA compared to controls. The U.S. group compared
908 samples from patients provided by the North American Rheumatoid
Arthritis Consortium (NARAC) — a group of investigators working
together to identify the genetic factors that contribute to RA — with
those from 1,282 people without RA (controls). The Swedish group
compared 676 samples from the Swedish Epidemiological Investigation
of Rheumatoid Arthritis (EIRA) with 673 controls.

"The whole-genome screening method lets us identify genes that
contribute to disease-susceptibility without imposing our preconceived
notions of the disease. We expected to come up with something new," says
Elaine F. Remmers, Ph.D., of the Genetics and Genomics Branch of
the NIAMS Intramural Research Program and an author of the study. "We
were thrilled to find out that TRAF1-C5 showed association not
only in the samples that we did with NARAC but also independently
in the Swedish group. By combining our information, we were able
to make a much stronger case [for a TRAF1-C5 association]. The
combined evidence was pretty impressive."

Remmers says the TRAF1-C5 region was the third of three major
susceptibility chromosomal regions for RA identified by their whole
genome screen. The first two, HLA-DRB1 and PTPN22, had already
been well established.

She says that it's not yet known how the genes in the TRAF1-C5
region influence RA risk. Nor can scientists say which of the two
genes is causing the disease. "Actually, both genes are very interesting
candidates," she says. "They both control inflammatory processes
that really are relevant for the disease, so we could easily envision
either of them playing a role — or both."

The hope is that by learning more about the genes and their role
in the disease, scientists may find clues to influencing treatment
of the disease. "We are hoping that we will find variants in either
of the genes that will lead us to new targets for therapy. Once
we understand how the RA-associated variants work, we may be able
interfere with the pathways the variants are influencing and either
prevent the disease or block its progression."

According to coauthor Daniel Kastner, M.D., Ph.D., NIAMS clinical
director and chief of the NIAMS Genetics and Genomics Branch, "The
success of the study can be attributed in part to the productive,
longstanding collaboration between NIAMS intramural researchers
and other scientists that the Institute supports around the country." NARAC
was established 10 years ago by coauthor Peter K. Gregersen, M.D.,
at the Feinstein Institute for Medical Research, the North Shore
Long Island Jewish Health System, in order to facilitate the collection
and analysis of RA genetic samples. Kastner was also a key early
member of the NARAC, as were many other investigators at several
academic health centers across the United States.

In addition to NIAMS, other support for the U.S. study came from
the National Center for Research Resources, the Arthritis Foundation,
grants from the Boas Family and the Eileen Ludwig Greenland Center
for Rheumatoid Arthritis (Feinstein Institute for Medical Research),
the Rosalind Russell Medical Research Center for Arthritis and
the Kirkland Scholar Award (University of California, San Francisco).

Support for the Swedish arm of the study came from the Swedish
Medical Research Council, the Swedish Council for Working Life
and Social Research, the King Gustaf Vís 80-Year Foundation, the
Swedish Rheumatism Foundation, the Stockholm County Council, the
AFA insurance company and the Agency for Science Technology and
Research, Singapore.

The mission of the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS), a part of the Department of Health and
Human Services' National Institutes of Health, is to support research
into the causes, treatment and prevention of arthritis and musculoskeletal
and skin diseases; the training of basic and clinical scientists
to carry out this research; and the dissemination of information
on research progress in these diseases. For more information about
NIAMS, call the information clearinghouse at (301) 495-4484 or
(877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

The National Center for Research Resources (NCRR) provides clinical
and translational researchers with the training and tools they
need to understand, detect, treat, and prevent a wide range of
diseases. For more information about NCRR, call 301-435-0888 or
visit www.ncrr.nih.gov.

The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.